Treatment of fibromyalgia and related fatigue syndromes using antagonists or partial agonists of 5HT1a receptors

ABSTRACT

The present invention provides a method for treating fibromyalgia and/or chronic fatigue syndrome by administering an antagonist or partial agonist of 5HT1a receptors.

FIELD OF THE INVENTION

[0001] The present invention provides a method for treating fibromyalgiaand related chronic fatigue syndromes by administering an antagonist orpartial agonist of 5HT1a receptors.

[0002] Fibromyalgia is a common clinical condition presenting withmusculoskeletal pain and tenderness often accompanied by fatigue(Goldberg D L 1995 Curr Opin Rheumatol 7, 127-135). It is seen both inPrimary Care and in Rheumatology Clinics. No specific treatment for thecondition is available and it is frequently regarded as a functionaldisorder which can run a chronic course.

[0003] Fibromyalgia and chronic fatigue syndromes share many clinicalcharacteristics. A majority of the patients are women and usually intheir thirties or forties on initial presentation. Over eighty percentin both diagnostic categories complain of fatigue, myalgia, arthralgia,recurrent headache and sleep difficulties (Moldofsky, 1993 CibaSymposium 173 p 262-279).

[0004] Conventional diagnostic evaluation does not reveal a structuralor biochemical abnormality in either fibromyalgia or related chronicfatigue syndrme. Attempts at elucidating the pathophysiology haveproduced inconsistent findings and a wide array of theories arecurrently put forward.

[0005] Studies indicate that a central 5HT1a receptor hypersensitivitymay be involved in the pathophysiology of chronic fatigue syndromeand/or fibromyalgia (Bakheit A M, Behan P O, Dinan T G 1992 BritishMedical Journal 304, 245-252). The release of prolactin from theanterior pituitary is under dopamine inhibition and under 5HTstimulation, probably at the level of the hypothalamus (Lamberts S W J,Macleod R M. Regulation of prolactin secretion at the level of thelactrotroph. Physiol Rev. 1990;70:279-318.). Buspirone is anazaspirodecanedione, which acts as a partial agonist at the 5HT1areceptor (Meltzer H Y, Maes M. Effects of buspirone on plasma prolactinand cortisol levels in major depressed and normal subjects. BiolPsychiat. 1994;35:316-323) and stimulates prolactin release. We haveestablished that prolactin release following buspirone challenge isenhanced in patients fulfilling criteria for chronic fatigue syndromeand fibromyalgia indicating 5HT1a receptor supersensitivity in theseconditions.

[0006] We have demonstrated this in a clinical study that extends ourprevious findings reported in U.S. Pat. No. 5,403,848 which relates tonon-ulcer dyspepsia.

[0007] A total of 12 subjects (9 female/3 male) and 12 healthycomparison subjects (9 female/3 male) gave fully informed consent totake part in the study. The mean±SD age of the patients was 33.6±8.2years (Range 2241) and of the comparison group 28.2±8.6 years (Range20-45). All patients fulfilled criteria for both fibromyalgia (ACRcriteria) and chronic fatigue syndrome (CDC criteria). At 0830 hsubjects had a cannula inserted in a forearm vein. Buspirone (30 mg) ormatching placebo was administered orally at 0900 h (Time 0). Blood wastaken at 0, 30, 60, 90, 120 and 180 min. Prolactin levels rose in allsubjects challenged with buspirone. The mean±SD AUC in patients was49±28 and in healthy subjects 27±35. This difference is significant atthe 0.05 level. Prolactin concentration between 60 and 90 min followingbuspirone administration provided the best discrimination between thetwo groups.

[0008] According to the present invention, what is required to treatfibromyagia and/or chronic fatigue syndrome is the administration ofeffective amounts of a substance that reduces the sensitivity of 5HT1areceptors and we have discovered that pindolol, which has affinity for5HT1a receptors has beneficial effects in subjects suffering fromfibromyalgia and/or chronic fatigue syndrome.

SUMMARY OF THE INVENTION

[0009] The present invention provides a means for prevention andtreatment of fibromyalgia and/or chronic fatigue syndrome byadministration of a substance that reduces the sensitivity of 5HT1areceptors. A preferred means is the administration of RS pindolol or asalt thereof. An especially preferred means is the administration of S(−) pindolol or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0010] As noted earlier, this invention can use any substance that is anantagonist or a partial agonist of 5HT1a receptors such that thesensitivity of 5HT1a receptors described above is reduced.

[0011] Pindolol is a beta adrenergic antagonist, used in the treatmentof hypertension and angina. It also has affinity for 5HT1a receptors ofa similar magnitude as its affinity for beta adrenergic receptors. Untilnow, no therapeutic applications of this phenomenon have beendiscovered. Pindolol is used therapeutically in hypertension and anginaas the racemic substance, RS pindolol. Most or all of thepharmacological effects of pindolol are possessed by the isomer S (−)pindolol. The present invention utilizes pindolol to reduce thesensitivity of 5HT1a receptors and as a result to provide the means forprevention and treatment of certain fatigue syndromes includingfibromyalgia. A preferred embodiment of the invention is the isomer S(−) pindolol or salts thereof.

[0012] The invention is likely to be effective in various presentationsof fibromyalgia and/or chronic fatigue syndrome in which there isaltered sensitivity of 5HT1a receptors.

[0013] Various pharmaceutical presentations are possible, including (butnot limited to) tablets, capsules, oral solutions and suspensions andparenteral solutions. Included are also pharmaceutical formulations fororal use in which the active substance is released in a controlled andslower fashion such that the treatment may be administered lessfrequently.

[0014] The usual doses of RS pindolol and S (−) pindolol will be in therange of 2.5 mg to 50 mg daily in single or divided doses, dependingupon the therapeutic response and the pharmaceutical form. The usualdoses of S (−) pindolol will be lesser than those of RS pindolol sincethe former will be more potent because it is responsible for most or allof the pharmacological effects.

[0015] The invention is intended for the treatment of mammals, includinghumans.

[0016] The ability of the invention to treat gastrointestinal diseasehas been demonstrated in a clinical study.

REFERENCES TO PREVIOUS PATENTS

[0017] T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,324,783

[0018] T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,403,848

EXAMPLE

[0019] Five patients with fibromyalgia (ACR criteria) who also metcriteria for chronic fatigue syndrome (CDC criteria) gave informedconsent to take part in this open label treatment study. All weretreated with pindolol 2.5 mg three times daily. Four of 5 patientsshowed a significant improvement in symptoms within 10 days ofcommencing treatment. There was a reduction in all symptoms and anincrease in energy levels and general wellbeing.

What is claimed is:
 1. A method for treating fibromyalgia comprisingadministrating of an effective amount of an antagonist or partialagonist of 5HT1a receptors.
 2. A method for treating chronic fatiguesyndrome comprising administrating of an effective amount of anantagonist or partial agonist of 5HT1a receptors.
 3. A method accordingto claim 1 employing an effective amount of the racemic substance RSpindolol or a salt thereof.
 4. A method according to claim 1 employingan effective amount of one of the enantiomers, S (−) pindolol or a saltthereof.
 5. A method according to claim 1 in which effective amounts ofRS-pindolol or S(−) pindolol or their salts are administered in apharmaceutical dosage form that permits rapid release of the activesubstances.
 6. A method for treating fibromyalgia comprisingadministrating of an effective amount of an antagonist or partialagonist of 5HT1a receptors in which effective amounts of RS pindolol orS(−) pindolol or their salts are administered in a pharmaceutical dosageform that releases the active substances in a controlled release formthat permits administration of the active substances at lesser frequencythan in claim
 5. 7. A method according to claim 1 in which the diseasesare characterised as fibromyalgia and/or chronic fatigue syndrome.
 8. Amethod according to claim 2 employing an effective amount of the racemicsubstance RS pindolol or a salt thereof.
 9. A method according to claim2 employing an effective amount of one of the enantiomers, S (−)pindolol or a salt thereof.
 10. A method according to claim 2 in whicheffective amounts of RS-pindolol or S(−) pindolol or their salts areadministered in a pharmaceutical dosage form that permits rapid releaseof the active substances.
 11. A method for treating chronic fatiguesyndrome comprising administrating of an effective amount of anantagonist or partial agonist of 5HT1a receptors in which effectiveamounts of RS pindolol or S(−) pindolol or their salts are administeredin a pharmaceutical dosage form that releases the active substances in acontrolled release form that permits administration of the activesubstances at lesser frequency than in claim
 5. 12. A method accordingto claim 2 in which the diseases are characterised as fibromyalgiaand/or chronic fatigue syndrome.